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m5C-dependent cross-regulation between nuclear reader ALYREF and writer NSUN2 promotes urothelial bladder cancer

Ning Wang1,2,3, Ri-Xin Chen4, Min-Hua Deng1,2

  • 1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510075, China.

Cell Death & Disease
|February 22, 2023
PubMed

Insights

5-methylcytosine (m5C) regulators are upregulated in bladder cancer. The reader ALYREF and writer NSUN2 crosstalk to promote tumor progression by stabilizing oncogenic RNAs, offering new therapeutic targets.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • 5-methylcytosine (m5C) methylation is crucial in human cancers.
  • m5C regulators are frequently altered in urothelial carcinoma of the bladder (UCB).

Purpose of the Study:

  • Investigate the role of m5C regulators, specifically NSUN2 and ALYREF, in UCB pathogenesis.
  • Elucidate the mechanism by which ALYREF promotes UCB cell proliferation and invasion.
  • Identify potential therapeutic targets for UCB.

Main Methods:

  • Analysis of The Cancer Genome Atlas and institutional UCB cohorts.
  • Patient-derived organoids and orthotopic xenograft mouse models.
  • Transcriptome-wide RNA bisulphite sequencing (BisSeq), RNA-sequencing (RNA-seq), and RNA Immunoprecipitation (RIP)-seq.

Main Results:

  • m5C regulators, including NSUN2 and ALYREF, are upregulated in UCB.
  • ALYREF enhances UCB cell proliferation and invasion in an m5C-dependent manner.
  • ALYREF binds to hypermethylated m5C sites on RABL6 and TK1 mRNA, promoting their splicing and stabilization.
  • ALYREF upregulates NSUN2 by recognizing its hypermethylated m5C site.
  • High coexpression of ALYREF/RABL6/TK1 axis correlates with poor patient survival.

Conclusions:

  • A novel m5C-dependent cross-regulation between ALYREF and NSUN2 drives UCB progression.
  • ALYREF activates oncogenic RNA through splicing and stabilization, mediated by m5C modification.
  • This pathway presents a promising therapeutic strategy for UCB.

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